The purpose of this study was to evaluate the effectiveness of CT colonography when patients were imaged in both the supine and prone positions. We evaluated whether imaging in two positions ...decreased the number of collapsed colonic segments and increased sensitivity for polyp detection.
Twenty-three patients underwent CT colonography in both the supine and prone positions. Colonic distention for each of the 46 scans was graded. Adequacy of distention for either position alone was compared with that of the combination of the two positions. Polyp data revealed by colonoscopy were reviewed, and the CT data were then retrospectively reviewed for polyp detection.
When each scan was considered alone without benefit of the scan obtained in the opposite position, 27 (58.7%) of 46 scans showed inadequate distention. When scans obtained in both positions were considered together, 20 (87.0%) of 23 patients had adequate distention with the grading system used. However, this value increased to 23 (100%) of 23 patients when the reasons for inadequate distention in the three patients were considered. Of the 27 polyps detected with colonoscopy, 21 (77.8%) were also detected retrospectively with CT colonography. Colonoscopy showed 20 polyps that were 5 mm or larger; nineteen (95.0%) of these 20 polyps were also detected retrospectively with CT colonography, nine (47.4%) of which were seen in only one position.
Use of both the supine and prone positions for patients undergoing CT colonography improves evaluation of the colon and increases sensitivity for polyp detection.
Both irinotecan (CPT-11, Camptosar) and paclitaxel have been shown to have single-agent activity in adenocarcinomas of the esophagus and gastric cardia. A phase I trial of the combination at UCLA ...established the dose as irinotecan at 225 mg/m2 and paclitaxel at 100 mg/m2 every 3 weeks. Preliminary data from a phase II trial of this regimen in adenocarcinomas of the gastroesophageal junction show good tolerability and promising activity (response rate of 27%), even in previously treated patients.
Importance Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). Objective To assess time to nadir and depth of nadir as ...surrogates for OS in metastatic colorectal cancer. Design, Setting, and Participants Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti–epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. Main Outcomes and Measures Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size–weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. Results For 14 chemotherapy comparisons in 4289 patients, theR2value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values ofR2were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti–epidermal growth factor receptor comparisons (2684 patients), corresponding values ofR2were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). Conclusions and Relevance In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.
Irinotecan (CPT-11 Camptosar) is an important new chemotherapeutic drug that demonstrates activity against a broad spectrum of malignancies, including carcinomas of the colon, stomach, and lung. ...Unfortunately, frequent and often severe gastrointestinal toxicities, particularly diarrhea, have limited its more widespread use. A cholinergic syndrome resulting from the inhibition of acetylcholinesterase activity by irinotecan is frequently seen within the first 24 hours after irinotecan administration but is easily controlled with atropine. Late diarrhea occurs in the majority of patients, however, and is National Cancer Institute (NCI) grade 3 or 4 in up to 40%. The late syndrome appears to be related to the effects on the bowel of SN-38, the active metabolite of irinotecan, which undergoes biliary excretion and inactivation. Early recognition and treatment of late diarrhea with high-dose loperamide have reduced, although not entirely eliminated, patient morbidity. Further study is needed to identify the mechanism of irinotecan-induced late diarrhea and to evaluate potential new therapies.
IntroductionT-VEC, an intralesionally-delivered oncolytic immunotherapy, is a herpes simplex virus-1 engineered to selectively replicate in tumors and stimulate an anti-tumor immune response through ...expression of GM-CSF. T-VEC has the ability to lyse various cancer cell types in vitro1. A Phase III study of T-VEC injected into skin, subcutaneous, or lymph node tumors versus subcutaneous GM-CSF in advanced melanoma demonstrated improved durable response rate for T-VEC, with regression of both injected and uninjected lesions2. To further explore if different types of cancers and locations might be treatable with T-VEC, this Phase I study evaluates whether primary and metastatic liver tumors may be safely and effectively injected with T-VEC.MethodsApproximately 100 patients will be enrolled. Primary objective: evaluate maximum tolerated dose (MTD) of intrahepatic injection of T-VEC by patient incidence of dose-limiting toxicities (DLTs). Key secondary objectives: overall safety, efficacy, and biodistribution of T-VEC. Key eligibility criteria: breast, colorectal, gastroesophageal, kidney, lung cancer or melanoma with liver metastases (non-HCC) or hepatocellular carcinoma (HCC); measurable liver tumors suitable for injection; ECOG performance status 0-1; life expectancy ≥5 months; ≥1 prior standard systemic anticancer therapy (non-HCC); Child-Pugh A-B7; no detectable hepatitis B/C viral load; not a candidate for surgery or locoregional therapy of liver tumors with curative intent or planned systemic anticancer therapy; tumor in < 1/3 of the liver; no macroscopic intravascular invasion. The study consists of two parts. Part 1: 3+3 dose escalation of 3 sequential dose cohorts each administering T-VEC in increasing concentrations (107 or 108 PFU/mL) and volumes (up to 4 or 8 mL). MTD for HCC is determined separately from non-HCC tumor types; HCC cohorts will not proceed until safety at respective dose levels are determined in non-HCC. Six T-VEC doses injected under ultrasound or computed tomography guidance q21 (±3) days are planned, with an investigator option to continue for up to 6 additional doses. The first dose of T-VEC in all dose cohorts is given at 106 PFU/mL. Part 2: 7 expansion cohorts for each cancer type with 10 patients each administered the MTD of T-VEC determined from Part 1.
Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy (1,2). The mechanisms underlying ...this acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs (3-6). The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations preexist at low levels in tumours with ostensibly wild-type KRASgenes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.
BACKGROUND. The safety and efficacy of the fully human antibody panitumumab was evaluated in patients with metastatic colorectal cancer refractory to available therapies. METHODS. This phase 2 ...open-label, multicenter study of panitumumab enrolled patients with metastatic colorectal cancer who had progressed on chemotherapy that included a fluoropyrimidine and irinotecan or oxaliplatin, or both. All patients had tumors with 10% 1+ epidermal growth factor receptor (EGFr) staining by immunohistochemistry. Patients were stratified into 2 strata (high or low staining intensity) and received intravenous panitumumab 2.5 mg/kg weekly 8 of every 9 weeks until disease progression or unacceptable toxicity. RESULTS. In all, 148 patients received panitumumab, 105 in the high EGFr stratum, 43 in the low EGFr stratum. Overall response by central review was 9% (95% confidence interval CI, 5%-15%) and was similar between strata. An additional 29% of patients had stable disease. Median progression-free survival was 14 weeks (95% CI, 8-16) and median overall survival was 9 months (95% CI, 6-10). Toxicities were manageable, with skin toxicity reported in 95% of patients (5% grade 3 or 4). Four patients discontinued therapy because of toxicity. No antipanitumumab antibodies were detected. One patient had an infusion reaction but was able to continue therapy. CONCLUSIONS. Panitumumab given weekly was well tolerated and had single-agent activity in previously treated patients with colorectal cancer. Dermatologic toxicity was common but rarely severe. Ongoing studies will determine panitumumab activity earlier in the course of treatment for colorectal cancer and in combination with other antineoplastic agents. Cancer 2007.
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